Cellular damage caused by oxidative stress has been implicated in the etiology of a number of diseases including many types of cancer and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and Amyotrophic Lateral Sclerosis. Understanding the cellular defensive response to such stress is critical. Experiments described in this proposal use the model system Saccharomyces cerevisiae to examine how cells change their gene expression program in response to oxidative stress. The main goal of this proposal is to determine the mechanism for oxidative stress-activated degradation of the yeast cyclin C homolog Ume3p. Ume3p normally functions to repress transcription of a large set of stress-induced genes. When cells are exposed to oxidative stress, Ume3p degradation is triggered, allowing expression of these genes. This stress-induced degradation is known to require Plclp (phospholipase C) and the PKCI MAP kinase pathway. This proposal is aimed at determining a) whether Plclp and Pkclp act in the same pathway, in a signal transduction pathway analogous to that seen in mammalian cells, b) which genes must be expressed for cells to survive oxidative stress and c) which genes are critical for sensing oxidative stress and triggering Ume3p destruction.